P353: NATURALLY SELECTED CD7-TARGETED CAR-T CELL THERAPY FOR RELAPSED OR REFRACTORY CENTRAL NERVOUS SYSTEM T-CELL LYMPHOBLASTIC LEUKEMIA/LYMPHOMA
Authors: Junfang Yang, Xian Zhang, Jingjing LI, Liyuan Qiu, Peihua Lu
Journal: HemaSphere (2023)

Background: Limited studies have demonstrated that CD7-targeted chimeric antigen receptor (CAR) T-cell therapy is effective and safe for T-cell acute lymphoblastic leukemia(T-ALL) and T-cell lymphoblastic lymphoma (T-LBL). However, it remains unclear whether CD7 CAR-T cells can penetrate the blood-brain barrier and be effective in treating central nervous system (CNS) T-ALL/LBL without increasing neurotoxicity. Aims: Here we explored the efficacy and safety of NS7CAR T-cells for relapsed or refractory (R/R) T-ALL/LBL with CNS involvement in phase I/II clinical trial (NCT04572308 &NCT04916860). Methods: Peripheral blood mononuclear cells were collected from patients by leukapheresis. A novel fratricide-resistant approach to derive naturally selected anti-CD7 CAR (NS7CAR) T cells was developed using lentiviral transduction of peripheral T cells that could overcome CD7-directed fratricide without additional genetic modifications. NS7CAR is a 2nd generation murine-based CAR-T containing 4-1BB and CD3ζ co-stimulatory domains. Intravenous fludarabine (30mg/m2/d) and cyclophosphamide (300mg/m2/d) were given to all patients on day -5 to day -3 prior to NS7 CAR T cells infusion. The proliferation of CAR-T cells in cerebrospinal fluid (CSF) was detected by flow cytometry (FCM). Results: From Dec. 2020 to Jun. 2022, 10 patients with CNS T-ALL (n=8) and T-LBL (n=2) were enrolled and received NS7CAR T cells. The median age was 14.5 (2-37) years old. Patient characteristics and clinical results were shown in Table 1. Three patients who relapsed from prior allogeneic hematopoietic stem cell transplantation (allo-HSCT) were also enrolled. At enrollment, 6 patients were CNS-3 status (blasts≥5/μL in CSF), and 4 were CNS-2 status (blasts<5/μL in CSF). Eight patients had leukemic cells both in bone marrow (BM) and CNS. Combined extramedullary disease (EMD) except for CNS involvements was found in 5 patients. The transduction efficiency was 91.2% (64.4%-97.4%). A single dose of NSCAR T cells was infused to patients at a low dose (5×105cells/kg, n=2), and a medium dose (1-1.5×106cells/kg, n=8). At a median of day 17 (day 14-day 51) post infusion, 10/10 (100%) achieved complete remission (CR) in CSF. The median follow-up time was 220 days (61-621 days). Two patients had early CNS relapse on day 56 (then received salvage transplant and were still alive at the last follow-up of day 412), and day 72, respectively. For the other 8 patients without CNS relapsed regardless of EMD/BM relapse, 5 who received consolidation/salvage allo-HSCT were still progression-free at a median follow-up of 286 days(188-621days), 1 lost follow-up on day 180, 1 relapsed in BM on day116 and withdrew for other clinical trials, and the other 1 remained CR on day 61. Mild cytokine release syndrome (CRS, ≤grade II) occurred in 8/10 (80%) patients, and 2/10(20%) patients had grade III CRS. One patient had grade IV neurotoxicity, and others did not develop neurotoxicity. All were controlled after the administration of corticosteroids and/or tocilizumab. Following infusion, the median maximum proliferation of NS7CAR T-cells in CSF was 22.56% (0-65.35%), which occurred on day 17(13-33) as detected by FCM. Summary/Conclusion: This study demonstrated that NS7 CAR-T is a promising method in treating patients who had R/R CNS T-ALL/LBL without increasing the risk of severe neurotoxicity. Safety was manageable. However, more data on additional patients and longer observation time are needed to fully evaluate the efficacy of NS7 CAR-T products in patients with CNS involvement.Keywords: CNS, CAR-T, T cell acute lymphoblastic leukemia, relapsed/refractory